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Inhibition of BET Proteins Modulates Immuno-Inflammatory Signaling Pathways in Primary Human Lung Cells
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A7740 - Inhibition of BET Proteins Modulates Immuno-Inflammatory Signaling Pathways in Primary Human Lung Cells
Author Block: H. Feldser, D. Chalupowicz, J. Kou, D. Carpenter, P. Landis, N. Goodwin, P. L. Podolin, W. Rumsey, Y. Sanchez; Respiratory Therapeutic Area, GlaxoSmithKline, Collegeville, PA, United States.
Rationale: The Bromodomain and Extra-Terminal Domain (BET) family of epigenetic transcriptional regulators controls multiple signaling pathways important for development of COPD. Inhibition of BET proteins has been shown to reduce inflammatory signaling and activate the oxidative stress response in multiple human cell types. Pharmacological inhibition of BET family proteins BRD4, BRD2 and BRD3 in lung cells may provide benefit to COPD patients through modulation of immuno-inflammatory, anti-oxidant and cytoprotective responses.
Methods: Human cells were sourced ethically; research use was in accord with the terms of the informed consents under an IRB-approved protocol. Primary human bronchial epithelial cells from healthy or COPD patient volunteers were grown in submerged culture or air-liquid interface to generate polarized epithelial monolayers. Alveolar macrophages were isolated from healthy donor lungs via bronchoalveolar lavage (BAL) and immediately plated for use. Cells were treated with BET inhibitors, and where indicated, exposed to cigarette smoke.
Results: BET inhibitors prevented cigarette smoke-induced apoptosis and reduced expression of cytokines and chemokines, including IL-6 and IL-8, in primary human bronchial epithelial cells. NRF2-dependent anti-oxidant genes, including HO-1, NQO1, and TXNRD1, were dose-dependently upregulated by BET inhibition in bronchial epithelial cells from healthy and COPD patients. Expression of immune signaling factors, including the B-cell proliferation factors BAFF and APRIL, was suppressed in primary bronchial epithelial cells grown at air-liquid interface, as well as in human alveolar macrophages.
Conclusions: Inhibition of BET proteins reduced inflammatory gene expression and activated the oxidative stress response in human lung cells. We demonstrate, for the first time, that BET inhibitors can also reduce expression of BAFF and APRIL in lung cells, which could blunt the enhanced B cell activity seen to correlate with lung functional decline in COPD patients. The multi-faceted benefits of BET inhibition in lung cells may offer a differentiated approach to the treatment of COPD.
Author Block: H. Feldser, D. Chalupowicz, J. Kou, D. Carpenter, P. Landis, N. Goodwin, P. L. Podolin, W. Rumsey, Y. Sanchez; Respiratory Therapeutic Area, GlaxoSmithKline, Collegeville, PA, United States.
Rationale: The Bromodomain and Extra-Terminal Domain (BET) family of epigenetic transcriptional regulators controls multiple signaling pathways important for development of COPD. Inhibition of BET proteins has been shown to reduce inflammatory signaling and activate the oxidative stress response in multiple human cell types. Pharmacological inhibition of BET family proteins BRD4, BRD2 and BRD3 in lung cells may provide benefit to COPD patients through modulation of immuno-inflammatory, anti-oxidant and cytoprotective responses.
Methods: Human cells were sourced ethically; research use was in accord with the terms of the informed consents under an IRB-approved protocol. Primary human bronchial epithelial cells from healthy or COPD patient volunteers were grown in submerged culture or air-liquid interface to generate polarized epithelial monolayers. Alveolar macrophages were isolated from healthy donor lungs via bronchoalveolar lavage (BAL) and immediately plated for use. Cells were treated with BET inhibitors, and where indicated, exposed to cigarette smoke.
Results: BET inhibitors prevented cigarette smoke-induced apoptosis and reduced expression of cytokines and chemokines, including IL-6 and IL-8, in primary human bronchial epithelial cells. NRF2-dependent anti-oxidant genes, including HO-1, NQO1, and TXNRD1, were dose-dependently upregulated by BET inhibition in bronchial epithelial cells from healthy and COPD patients. Expression of immune signaling factors, including the B-cell proliferation factors BAFF and APRIL, was suppressed in primary bronchial epithelial cells grown at air-liquid interface, as well as in human alveolar macrophages.
Conclusions: Inhibition of BET proteins reduced inflammatory gene expression and activated the oxidative stress response in human lung cells. We demonstrate, for the first time, that BET inhibitors can also reduce expression of BAFF and APRIL in lung cells, which could blunt the enhanced B cell activity seen to correlate with lung functional decline in COPD patients. The multi-faceted benefits of BET inhibition in lung cells may offer a differentiated approach to the treatment of COPD.
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